Predominant symptom of Parkinson's disease, a neurodegenerative disorder, is extrapyramidal dysfunction resulted from dopamine depletion in the basal ganglia following degenaration of nigrostriatal projection. Due to apparent therapeutic potentials of dopamine replacement, combined application of L-DOPA (levodopa, a dopamine precursor) and dopaminergic agents has been a major strategy in the treatment for Parkinson's disease. Therapeutic drugs for Parkinson's disease launched or on the development include L-DOPA, dopamine agonists, dopamine release enhancers (amantadine), anti-cholinergic drugs, L-DOPA metabolic inhibitors (MAO-B, COMT inhibitors) and norepinephrine precursors. The order of priority for using these drugs is: (amantadine and anti-cholinergic drugs), dopamine agonists and (L-DOPA, or L-DOPA+MAO-B, COMT inhibitors). L-DOPA is the most popular drug, but its long-term application leads to loss of drug efficacy such as “wearing-off” and “on-off” and the onset of dyskinesia. Therefore, the dosage of L-DOPA should be as low as possible through combined application with other drugs. In addition, since L-DOPA is an oral agent, considering the “QOL” of patients, co-administrated drugs are desirable to be of the same type.
L-pyroglutamyl-L-histidyl-L-prolinamide (p-Glu-His-Pro-NH2) known as TRH (thyrotropin releasing hormone) is a hormone discovered in the hypothalamus and consisting of 3 amino acid residues. This hormone is suggested to act through TRH receptors. TRH is known not only to promote the secretion of TSH (tyrotoropin stimulating hormone) and prolactin, but also to have cerebral nerve activation (stimulation of motor function and the like), effects on sympathetic nervous system (elevation of blood pressure, stimulation of respiratory and the like), effects on spinal function (stimulation of spinal motoneuron and the like), effects on central nervous system (antidepressant activity and the like) and peripheral actions (suppression of gastric acid secretion, stimulation of glucagon secretion and the like). Having such various activities, TRH has been investigated for the clinical use, and is being used as an intravenous injection for treating spinocerebellar degeneration for purposes of improvement of motility disturbance and cognitive disturbance accompanied by brain functional disturbance (Sofue, Kanazawa, Ogawa, “Neuropeptide” '91, Medicalreview).
The structure of TRH derivatives with more enhanced activities for central nervous system generally consists of 3 amino acid residues as well as TRH or their derivatives. Most of the derivatives have a molecular weight of about 370 to 430. For example, they are described in the following documents: J. Med. Chem, 33, 2130–2137 (1990) and JP Laid-Open (Kokai) No. 86/33197 (e.g.: Taltirelin; TA-0910); Biomedical Research 14 (5) 317–328 (1993) and ZA7505956 (montirelin; CG3703); Arzneim.-Forsch/Drug Res., 39, 297–303 (1989) and JP Laid-Open (Kokai) No. 81/8354 (posatirelin; RGH2202); Eur. J. Pharmacol. 276, 177–182 (1995) and JP Laid-Open (Kokai) No. 91/236397 (e.g.: JTP-2942); JP Patent-Publication (Kokoku) No. 90/36574 (e.g.:1-methyl-L-4,5-dihydroorotyl-L-histidyl-L-prolinamide): JP Laid-Open (Kokai) No. 77/116465 (e.g.: 2,3,4, 5-tetrahydro-2-oxo-L-5-furancarbonyl-L-histidyl-L-prolinamide); JP Patent-Publication (Kokoku) No. 91/236397 (e.g.: (1S,2R)-2-methyl-4-oxocyclopentylcarbonyl-L-histidyl-L-prolinamide); JP Patent-Publication (Kokoku) No. 84/36612 (e.g.: orotyl-L-histidyl-L-prolinamide); Eur. J. Pharmacol., 271, 357 (1994) (e.g.: TRH-SR); JP Laid-Open (Kokai) No. 77/3080; Eur. J. Pharmacol. 277, 63–69 (1995) and JP Laid-Open (Kokai) No. 85/27982 (e.g.: azetirelin; YM14673); JP Laid-Open (Kokai) No. 85/23326 (e.g.: DN1417); JP Laid-Open (Kokai) No. 87/234029; JP Laid-Open (Kokai) No. 81/8354; WO96/11209; WO98/08867, and the like. Compounds exemplified in examples in the present invention are described in WO98/08867.
It is described in “Journal of the Neurological Science 159 (1998) 135–139” that an intraperitoneal injection of TRH-SH (sustained release microspheres of TRH, Takeda Chemical Industries, Ltd.) increased striatal dopamine levels in Japanese encephalitis virus (JEV)-induced post-encephalitic parkinsonism mice compared with untreated group. However, it is described in the paper that mechanisms underlying post-encephalitic parkinsonism were different from that for Parkinson's disease. Further it is described that TRH-SH may be used as a supportive drug of L-DOPA, without mentioning the increase of L-DOPA activities or the synergistic action in combination use. Furthermore, TRH-SH is essentially a drug for injection and the possibility of oral administration is not mentioned there.